The etiology of insulin dependent diabetes mellitus in humans seems to entail an interaction between a susceptible genotype and an environmental stress. The recessive mutation diabetes in the mouse is consequently of interest as a model system for understanding such interactions. The diabetes gene itself does not determine whether a mild or a severe diabetes syndrome will result; rather, its expression creates a diabetogenic environment that demands an increased insulin supply. The response to this stress is determined by other genetic factors in the inbred strain background. Thus, diabetes gene expression in certain inbred strain (C57BL/KsJ, CBA/J) is characterized by an abortive attempt to increase insulin supply, with insulinopenia, beta cell necrosis, and severe diabetes resulting. On the contrary, in other inbred strains (C57BL/6J, 129/J) the diabetogenic stress is met by an enhanced insulin secretion that is sustained indefinitely. An understanding of the action of modifying genes that change the course of murine diabetes from a severe juvenile-onset type to a mid maturity-onset type would be an important contribution to the understanding of diabetes in man. We have developed a therapeutic high protein - no carbohydrate diet which permits full expression of the diabetes gene, but which nevertheless blocks beta cell necrosis and diabetes development in the otherwise-susceptible C57BL/Ks strain. To test how carbohydrate might interact with the C57BL/Ks genome to stress beta cells, we established beta cell cultures from pre-diabetic mice and normal controls. We found that high concentrations of glucose could rapidly induce the expression of an endogenous retrovirus particle. The aim of this research is now to test in vivo and in vitro whether diabetes induction can be correlated with constitutive ability of the C57BL/Ks and CBA (but not the C57BL/6 or 129/J) strains to express endogenous proteins (viral or other) in beta cells chronically stimulated by a hyperglycemic environment. Experiments have been proposed to test the hypothesis that chronically hyperactive beta cells may be induced to express proteins that are normally not produced ("eclipsed" antigens). The experiments have been designed to test the possibility that such antigens are not recognized as "self" by the host immune system and can lead to beta cell destruction by autoimmune mechanisms.